This proposal continues to investigate the effects of chlorinated hydrocarbons (CHs) in mammals. Though emphasis has been placed on studying the estrogenic action of these compounds, certain nonhormonal effects of CHs, relating to potential for long range toxicity, will also be examined. The early estrogenic events to be examined are interactions of CHs at the estrogenic receptor level and induction of ornithine decarboxylase (ODC). A method will be developed to study induction of ODC by CHs in vitro, using uteri and human breast tumors in culture. Additionally, induction of the progesterone receptor and peroxidase, events requiring longer time for expression, will be studied. It is planned to determine whether estrogenic activity of a given CH is due to the parent compound per se or whether this activity is expressed via metabolites of the respective CH. The possibility that the estrogenic activity is associated with contaminants, present in commercial preparations of a given CH, will be explored. In particular, the structurally identified contaminants of methoxychlor will be examined. With DMBA-induced mammary tumors in rats, the growth promoting or inhibiting characteristics of CHs will be examined. The potential for long range toxicity of CHs will include the determination whether certain CHs undergo metabolic activation yielding in vivo and in vitro covalent binding to proteins, RNA and DNA and whether these CHs are mutagenic. Also the possibility that metabolic activation of CHs in the liver will produce an in situ destruction of the hepatic "estrogen receptor" will be examined. Additionally, the effect of exposing neonatal animals to CHs on sexual development at the adult stage will be examined. The above studies are designed to establish whether there is a strict correlation between the estrogenic potencies of CHs and animal toxicity.